Methods and compositions for treating malignant tumors associated with KRAS mutation

Abstract

This invention provides methods and compositions for preventing, treating or ameliorating one or more symptoms of a malignant tumor, which may be associated with KRAS mutation in a mammal in need thereof, by administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π.

What is claimed is: 
     
       1. A method for preventing, treating or ameliorating one or more symptoms of a malignant tumor associated with KRAS mutation in a mammal in need thereof, the method consisting of:
 identifying a tumor cell in the mammal, the tumor cell comprising at least one of: (i) a mutation of a KRAS gene, and (ii) an aberrant expression level of KRAS protein compared to a non-tumor cell of the same tissue; and 
 administering to the mammal a therapeutically effective amount of a composition comprising one or more RNAi molecules that are active in reducing expression of GST-π, wherein the composition comprises only one active ingredient and the active ingredient is the RNAi molecules, 
 wherein the tumor cell comprises an increased level of expression of wild type KRAS protein compared to that in a non-tumor cell of the same tissue, and 
 wherein the malignant tumor is a carcinoma selected from the group consisting of lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, colorectal carcinoma, breast cancer, and fibrosarcoma. 
 
     
     
       2. The method of  claim 1 , wherein the mammal is a human and the GST-π is a human GST-π. 
     
     
       3. The method of  claim 1 , wherein the RNAi molecule is a siRNA or shRNA. 
     
     
       4. The method of  claim 1 , wherein the RNAi molecules comprise a duplex region comprising a nucleotide sequence corresponding to a target sequence of SEQ ID NO:287. 
     
     
       5. The method of  claim 1 , wherein the RNAi molecule decreases expression of GST-π in the mammal. 
     
     
       6. The method of  claim 1 , wherein the administration decreases expression of GST-π in the tumor cell by at least 5% for at least 5 days. 
     
     
       7. The method of  claim 1 , wherein the administration decreases the volume of the malignant tumor in the mammal by at least 5%, or at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%. 
     
     
       8. The method of  claim 1 , wherein the method reduces one or more symptoms of the malignant tumor, or delays or terminates the progression of the malignant tumor. 
     
     
       9. The method of  claim 1 , wherein the administration reduces growth of malignant tumor cells in the subject. 
     
     
       10. The method of  claim 1 , wherein the administration reduces growth for at least 2%, or at least 5%, or at least 10%, or at least 15%, or at least 20% of the malignant tumor cells in the subject. 
     
     
       11. The method of  claim 1 , wherein the tumor cell over-expresses wild-type GST-π RNA or protein compared to non-tumor cells of the same tissue. 
     
     
       12. The method of  claim 1 , wherein the tumor cell comprises a mutation in a KRAS protein at one or more of residues 12, 13 and 61. 
     
     
       13. The method of  claim 1 , wherein the tumor cell comprises a mutation in a KRAS protein and the tumor is a cancer selected from lung cancer, colon cancer, and pancreatic cancer. 
     
     
       14. The method of  claim 1 , wherein the malignant tumor is located in an anatomical region selected from the group of lung, colon, pancreas, gallbladder, liver, breast, and any combination thereof. 
     
     
       15. The method of  claim 1 , wherein the administration is performed from 1 to 12 times per day. 
     
     
       16. The method of  claim 1 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6 or 7 days. 
     
     
       17. The method of  claim 1 , wherein the administration is performed for a duration of 1, 2, 3, 4, 5, 6, 8, 10 or 12 weeks. 
     
     
       18. The method of  claim 1 , wherein the administration is a dose of from 0.01 to 2 mg/kg of the RNAi molecules at least once per day for a period up to twelve weeks. 
     
     
       19. The method of  claim 1 , wherein the administration provides a mean AUC(0-last) of from 1 to 1000 ug*min/mL and a mean C max  of from 0.1 to 50 ug/mL for the GST-π RNAi molecule. 
     
     
       20. The method of  claim 1 , wherein the administration is intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, oral, topical, infusion, or inhalation.